CD4+ helper T (TH) lymphocytes are essential organizers of adaptive immune responses and key mediators in immune-mediated autoimmune and allergic diseases. Upon activation by the antigen-presenting cells (ARC), naive TH cells undergo clonal expansion and functional differentiation into cytokine-secreting effector cells. Effector TH cells have been historically classified into TH1 and TH2 subsets. TH1 cells make interferon g (IFNg) and regulate antigen presentation and cellular immunity. TH2 cells, on the other hand, secrete IL-4, -5 and -13, which together regulate humoral and anti-parasite immunity. The cytokine microenvironment during TH activation determines TH effector differentiation, through selective signal transducer and activator of transcription (STAT) proteins leading to expression of lineage-specific master transcription factors. Recently, a novel TH subset, named THIL-17, TH17 or THi, that make IL-17 has emerged as critical regulators of tissue inflammation. We found that TH17/THJ cells are a distinct lineage of TH cells from TH1 and TH2 cells and TH17/THi differentiation is negatively regulated by IFNg and IL-4. IL-6 and IL-23 synergize in TH17/TH1 differentiation through Stat3. This new grant aims at investigating the molecular programs governing TH17/THi differentiation. Our central hypothesis is that cytokine mediated STATS activation initiates TH17/THi-specific transcriptional and epigenetic programs. We will first investigate the function of STATS in TH17/THi differentiation and test if STATS functions to upregulate RORa and RORc during TH17/THJ differentiation. Secondly, we will investigate the function of RORa in TH17/THJ differentiation. Lastly, we will Investigate the molecular specification of TH17/THJ and inducible regulatory T (iTreg) cells. These studies will greatly benefit our understanding of the molecular programs governing TH17/THi differentiation and may suggest novel treatments of TH17/THi-mediated immune diseases.